In situ repolarization of tumor-associated macrophages with synergic nanoformulation to reverse immunosuppressive TME in mouse breast cancer for cancer therapy.

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Fenamates: Forgotten treasure for cancer treatment and prevention: Mechanisms of action, structural modification, and bright future.

Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/ß-catenin, TGF-ß, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.

Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment.

BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.

The Combination of SHOX2 and RASSF1A DNA Methylation Had a Diagnostic Value in Pulmonary Nodules and Early Lung Cancer.

INTRODUCTION: The study explored the effects of SHOX2 and RASSF1A DNA methylation in lung cancer (LC). METHOD: Bronchoalveolar lavage fluid (BALF) samples as well as LC and normal adjacent tissues were collected from 72 LC patients and 35 patients with benign pulmonary nodules. Quantitative analysis of SHOX2 and RASSF1A DNA methylation was performed in benign pulmonary nodules and different stages of LC. The diagnostic value of SHOX2 and RASSF1A DNA methylation in LC and benign pulmonary nodules was determined by receiver operating characteristics analysis. Gain/loss-of-function experiments were constructed in LC cells and mouse models of xenograft and pulmonary nodule metastasis. The levels of SHOX2 and transfer-associated genes were tested through quantitative reverse transcription polymerase chain reaction and Western blot. Malignant phenotype of LC cells was assessed by functional experiment. The tumor volume and weight of mice in xenograft models were measured. Pulmonary nodule metastasis was determined through HE staining assay. 5-azacytidine appeared as a positive control drug. RESULT: SHOX2 DNA methylation or RASSF1A DNA methylation had diagnostic efficiency in pulmonary nodules and early LC, with the two combined having better diagnostic value. SHOX2 expression was upregulated in LC. Similar to 5-azacytidine, SHOX2 knockdown inhibited LC cell viability, migration, and invasion in vitro as well as restrained LC tumorigenesis and pulmonary nodule metastasis in vivo, whereas overexpressed SHOX2 had the opposite effects. CONCLUSION: The combination of SHOX2 and RASSF1A DNA methylation had a diagnostic value in pulmonary nodules and early LC. SHOX2 positively modulated the tumorigenesis and metastasis of LC by regulating DNA methylation processes.

The triangular relationship between traditional Chinese medicines, intestinal flora, and colorectal cancer.

Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.

Progress in the treatment of malignant ascites.

Malignant ascites occurs as a symptom of the terminal stage of cancer, affecting the quality of life through abdominal distension, pain, nausea, anorexia, dyspnea and other symptoms. We describe the current main drug treatments in addition to surgery according to the traditional and new strategies. Traditional treatments were based on anti-tumor chemotherapy and traditional Chinese medicine treatments, as well as diuretics to relieve the patient's symptoms. New treatments mainly involve photothermal therapy, intestinal therapy and targeted immunity. This study emphasizes that both traditional and new therapies have certain advantages and disadvantages, and medication should be adjusted according to different periods of use and different patients. In conclusion, this article reviews the literature to systematically describe the primary treatment modalities for malignant ascites.

Transcriptome analysis reveals molecular mechanisms of lymphocystis formation caused by lymphocystis disease virus infection in flounder (Paralichthys olivaceus).

Lymphocystis disease is frequently prevalent and transmissible in various teleost species worldwide due to lymphocystis disease virus (LCDV) infection, causing unsightly growths of benign lymphocystis nodules in fish and resulting in huge economic losses to aquaculture industry. However, the molecular mechanism of lymphocystis formation is unclear. In this study, LCDV was firstly detected in naturally infected flounder (Paralichthys olivaceus) by PCR, histopathological, and immunological techniques. To further understand lymphocystis formation, transcriptome sequencing of skin nodule tissue was performed by using healthy flounder skin as a control. In total, RNA-seq produced 99.36%-99.71% clean reads of raw reads, of which 91.11%-92.89% reads were successfully matched to the flounder genome. The transcriptome data showed good reproducibility between samples, with 3781 up-regulated and 2280 down-regulated differentially expressed genes. GSEA analysis revealed activation of Wnt signaling pathway, Hedgehog signaling pathway, Cell cycle, and Basal cell carcinoma associated with nodule formation. These pathways were analyzed to interact with multiple viral infection and tumor formation pathways. Heat map and protein interaction analysis revealed that these pathways regulated the expression of cell cycle-related genes such as ccnd1 and ccnd2 through key genes including ctnnb1, lef1, tcf3, gli2, and gli3 to promote cell proliferation. Additionally, cGMP-PKG signaling pathway, Calcium signaling pathway, ECM-receptor interaction, and Cytokine-cytokine receptor interaction associated with nodule formation were significantly down-regulated. Among these pathways, tnfsf12, tnfrsf1a, and tnfrsf19, associated with pro-apoptosis, and vdac2, which promotes viral replication by inhibiting apoptosis, were significantly up-regulated. Visual analysis revealed significant down-regulation of cytc, which expresses the pro-apoptotic protein cytochrome C, as well as phb and phb2, which have anti-tumor activity, however, casp3 was significantly up-regulated. Moreover, bcl9, bcl11a, and bcl-xl, which promote cell proliferation and inhibit apoptosis, were significantly upregulated, as were fgfr1, fgfr2, and fgfr3, which are related to tumor formation. Furthermore, RNA-seq data were validated by qRT-PCR, and LCDV copy numbers and expression patterns of focused genes in various tissues were also investigated. These results clarified the pathways and differentially expressed genes associated with lymphocystis nodule development caused by LCDV infection in flounder for the first time, providing a new breakthrough in molecular mechanisms of lymphocystis formation in fish.

Identification of a Novel Prognostic Signature Based on N-Linked Glycosylation and Its Correlation with Immunotherapy Response in Hepatocellular Carcinoma.

Background: The complex tumor microenvironment of hepatocellular carcinoma (HCC) has led to a low response to immune checkpoints inhibitors (ICIs) and a poor prognosis. PD-L1, as one of the indications for ICIs, is rich in glycosylation modifications, which result in untimely ICIs. Our study constructed a prognostic model based on N-linked glycosylation related genes for predicting the prognosis and the response to ICIs. Methods: The list of N-linked glycosylation related genes is from the AmiGO2 database. The patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were enrolled. The Cox regression was performed to develop a prognostic model and patients were divided into a low- and high-risk subgroups. The role of signature in HCC was well investigated by prognostic analysis, gene set enrichment analysis, and immune infiltration analysis. 21 recurrent HCC patients who received postoperative adjuvant ICIs were recruited to evaluate the relationship between immunotherapy response and the signature. In vitro studies were conducted to investigate the oncogenic effects of DDOST, STT3A and TMEM165 in HCC. Results: 59 N-linked glycosylation related differentially expressed genes were screened from HCC and normal tissues in the TCGA cohort. The prognostic model was developed with DDOST, STT3A and TMEM165. The risk score could be an independent prognostic factor. Patients in the high-risk subgroup showed a worse prognosis than patients in the low-risk one. ssGSEA showed that patients in the low-risk subgroup tended to be in the immune-activated state, with higher levels of B cell and macrophage cell infiltrations and lower levels of regulatory T cell (Treg) infiltrations in both TCGC and GEO cohorts. Immunohistochemistry studies showed that DDOST, STT3A and TMEM165 are highly expressed in tumor tissues and patients with a high-risk score correlated with poor progression free survival and worse immunotherapeutic response. Furthermore, the proliferation of HCC cells was reduced after the knockdown of DDOST, as well as upon the knockdown of STT3A and TMEM165. Conclusion: In this study, we establish that the risk model based on N-linked glycosylation related genes could efficiently predict the prognosis and tumor microenvironment immune state of HCC patients, and the risk score could serve as a novel indicator of immunotherapy.

Design, synthesis, and biological evaluation of 1-styrenyl isoquinoline derivatives for anti-hepatocellular carcinoma activity and effect on mitochondria.

In this study, 18 derivatives of 1-styrene-isoquinoline were designed and synthesized from resveratrol and isoquinoline. The IC50 of compound 1c against Huh7 and SK-Hep-1 cells were 2.52 µM and 4.20 µM, respectively. Mice were treated with 650 mg/kg compound 1c, and the survival status of mice was good. Further studies showed that compound 1c could inhibit cell proliferation by arresting the cell cycle in the G2/M phase, induce cell apoptosis, and inhibit cell migration and invasion by regulating epithelial-mesenchymal transition (EMT). It is worth noting that numbers of studies have pointed that resveratrol can trigger mitochondrial apoptosis to induce apoptosis of cancer cells. Therefore, we investigated the mechanism of compound 1c induced apoptosis of Huh7 and SK-Hep-1 cells. The results indicated that compound 1c could regulate the expression of proteins which are related to mitochondrial apoptosis pathway and inhibit the phosphorylation of PI3K/Akt/mTOR signaling pathway. In addition, compound 1c could inhibit the growth of Huh7-xenografts, and perform a tumor inhibitory rate of 41.44% when administered 30 mg/kg once a day. This work provides a potential anti-hepatocellular carcinoma compound that warrants further investigation.

Neuroprotective Effects of an N-Salicyloyl Tryptamine Derivative against Cerebral Ischemia/Reperfusion Injury.

Cerebral ischemia/reperfusion (I/R) injury is a key reason for the poor prognosis of ischemic stroke. As only a few neuroprotective medications for cerebral I/R injury have been applied in the clinic, it is necessary to design a new therapeutic strategy to treat cerebral I/R injury. The N-salicyloyl tryptamine derivative LZWL02003, synthesized from melatonin and salicylic acid, exhibits a wide range of biological properties. In this study, we assessed the neuroprotective capabilities of LZWL02003 in vivo and in vitro and investigated its possible mechanisms. Oxygen-glucose deprivation/reoxygenation was utilized to create an in vitro model of cerebral I/R damage. Middle cerebral artery occlusion/reperfusion was employed to imitate cerebral I/R injury in vivo. Neuronal apoptosis, oxidative stress, mitochondrial dysfunction, and neuroinflammation are associated with the pathogenesis of cerebral I/R injury. Our findings demonstrated that LZWL02003 upregulated the expression of Bcl-2 and downregulated the expression of Bax, thus maintaining the homeostasis of Bcl-2/Bax proteins and preventing apoptosis. LZWL02003 also reduced oxidative stress by reducing malondialdehyde and reactive oxygen species levels, increasing the superoxide dismutase activity, and resolving mitochondrial malfunction. LZWL02003 can lower interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 levels, which in turn suppress neuroinflammation. Activation of the nuclear factor-kappa B (NF-κB) pathway is involved in various pathophysiologies, including cerebral I/R injury. We discovered that LZWL02003 suppressed the phosphorylation activation of NF-κB pathway-related proteins and decreased the nuclear translocation of NF-κB p65 subunits. Taken together, our results suggest that LZWL02003 is a neuroprotective drug with pleiotropic effects and may be a candidate for treating cerebral I/R injury.

Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models.

Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, α-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/ß-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.

Emerging advances in engineered macrophages for tumor immunotherapy.

Macrophages are versatile antigen-presenting cells. Recent studies suggest that engineered modifications of macrophages may confer better tumor therapy. Genetic engineering of macrophages with specific chimeric antigen receptors offers new possibilities for treatment of solid tumors and has received significant attention. In vitro gene editing of macrophages and infusion into the body can inhibit the immunosuppressive effect of the tumor microenvironment in solid tumors. This strategy is flexible and can be applied to all stages of cancer treatment. In contrast, nongenetic engineering tools are used to block relevant signaling pathways in immunosuppressive responses. In addition, macrophages can be loaded with drugs and engineered into cellular drug delivery systems. Here, we analyze the effect of the chimeric antigen receptor platform on macrophages and other existing engineering modifications of macrophages, highlighting their status, challenges and future perspectives. Indeed, our analyses show that new approaches in the treatment of solid tumors will likely exploit macrophages, an innate immune cell.

Intra-Tumoral Secondary Follicle-like Tertiary Lymphoid Structures Are Associated with a Superior Prognosis of Overall Survival of Perihilar Cholangiocarcinoma.

Ectopic lymphoid structures termed tertiary lymphoid structures (TLSs) have an immunomodulatory function and positively affect prognosis in certain cancers. However, their clinical relevance and prognostic utility in perihilar cholangiocarcinoma (pCCA) are unknown. Therefore, determining the involvement and prognostic utility of TLSs in pCCA is the aim of this study. Ninety-three patients with surgically resected pCCA were included retrospectively. Hematoxylin and eosin and immunohistochemical staining identified and classified the TLSs, and multiplex immunofluorescence determined the TLS composition in the pCCA sample. The correlations between clinical features and TLSs were analyzed using either Fisher's exact test or the Chi-squared test. Recurrence-free survival (RFS) and overall survival (OS) correlations with TLSs were analyzed using Cox regression and Kaplan-Meier analyses. We identified TLSs in 86% of patients with pCCA, including lymphoid aggregates (6.45%), primary (13.98%) and secondary follicles (65.59%). Patients with intra-tumoral secondary follicle-like TLSs (S-TLSs) had better OS (p = 0.003) and RFS (p = 0.0313). The multivariate analysis identified the presence of S-TLSs as a good independent prognostic indicator for OS but not for RFS. Interestingly, the presence of S-TLS only indicated better 5-year OS in 54 patients without lymph node metastasis (LNM-, p = 0.0232) but not in the 39 patients with lymph node metastasis (LNM+, p = 0.1244). Intra-tumoral S-TLSs predicted longer OS in patients with surgically resected pCCA, suggesting intra-tumoral S-TLSs' contribution to effective antitumor immunity and that S-TLSs hold promise for diagnostic and therapeutic development in pCCA.

Higher Adherence to Healthy Lifestyle Score Is Associated with Lower Odds of Non-Alcoholic Fatty Liver Disease.

Growing evidence supports that individual lifestyle factors contribute to the development of non-alcoholic fatty liver disease (NAFLD) without considering the coexistence and synergistic effect of lifestyle factors. Our aim is to derive a healthy lifestyle score (HLS) and estimate its association with NAFLD. In this nationwide cross-sectional study, we derived a five-item HLS including dietary pattern, body mass index, physical activity, cigarette smoking, and sleep duration. NAFLD and clinically significant fibrosis (CSF) were assessed based on vibration-controlled transient elastography (VCTE). Liver function parameters were also tested. Multivariable logistic and linear regressions were applied to investigate the association between HLS and liver diseases. Of the 3893 participants with VCTE examination, approximately 14.1% of participants possessed zero or one healthy lifestyle, 62.5% possessed two or three healthy lifestyles, and 23.4% possessed four or five healthy lifestyles. Compared with participants with a low HLS (0−1 score), the adjusted odds ratios and 95% confidence intervals for those with a high HLS (4−5 score) were 0.25 (0.19~0.33, Ptrend < 0.001) for NAFLD and 0.30 (0.18~0.50, Ptrend < 0.001) for CSF. HLS was positively associated with albumin, total protein, and total bilirubin (all Ptrend ≤ 0.001), and was inversely associated with globulin, alanine aminotransferase, and gamma-glutamyl transaminase (all Ptrend ≤ 0.003). Higher adherence to HLS is associated with lower odds of NAFLD and CSF and may improve liver function. Strategies for the promotion of a healthy lifestyle should be considered as part of NAFLD prevention.

Recent advance on pleiotropic cholinesterase inhibitors bearing amyloid modulation efficacy.

Due to the hugely important roles of neurotransmitter acetylcholine (ACh) and amyloid-ß (Aß) in the pathogenesis of Alzheimer's disease (AD), the development of multi-target directed ligands (MTDLs) focused on cholinesterase (ChE) and Aß becomes one of the most attractive strategies for combating AD. To date, numerous preclinical studies toward multifunctional conjugates bearing ChE inhibition and anti-Aß aggregation have been reported. Noteworthily, most of the reported multifunctional cholinesterase inhibitors are carbamate-based compounds due to the initial properties of carbamate moiety. However, because their easy hydrolysis in vivo and the instability of the compound-enzyme conjugate, the mechanism of action of these compounds is rare. Thus, non-carbamate compounds are of great need for developing novel cholinesterase inhibitors. Besides, given that Aß accumulation begins to occur 10-15 years before AD onset, modulating Aß is ineffective only in inhibiting its aggregation but not eliminate the already accumulated Aß if treatment is started when the patient has been diagnosed as AD. Considering the limitation of current Aß accumulation modulators in ameliorating cognitive deficits and ineffectiveness of ChE inhibitors in blocking disease progression, the development of a practically valuable strategy with multiple pharmaceutical properties including ChE inhibition and Aß modulation for treating AD is indispensable. In this review, we focus on summarizing the scaffold characteristics of reported non-carbamate cholinesterase inhibitors with Aß modulation since 2020, and understanding the ingenious multifunctional drug design ideas to accelerate the pace of obtaining more efficient anti-AD drugs in the future.

Discovery of dual inhibitors of topoisomerase I and Cyclooxygenase-2 for colon cancer therapy.

Novel tolfenamic acid derivatives based on the structure of I-1 were designed and synthesized to improve its poor target inhibition and solubility. Among them, W10 was identified as a potent dual-target inhibitor of Topo I (IC50 = 0.90 ± 0.17 µM) and COX-2 (IC50 = 2.31 ± 0.07 µM) with improved water solubility (32.33 µg/mL). Moreover, W10 also exhibited fairly potent anti-proliferative and pro-apoptosis activity via the mitochondrial pathway, as well as suppressed aberrant NF-κB/IκB activation in colon cancer cells in vitro. Additionally, W10 possessed favorable pharmacokinetic properties and excellent antitumor effects in vivo. In general, our study has demonstrated the potency of a novel Topo I/COX-2 dual inhibitor, which can potentially be developed into a chemotherapeutic candidate for colon cancer.

N-2-(Phenylamino) Benzamide Derivatives as Dual Inhibitors of COX-2 and Topo I Deter Gastrointestinal Cancers via Targeting Inflammation and Tumor Progression.

Given the close association between inflammation and cancer, combining anti-inflammation therapy is prominent to improve the anticancer effect. Based on I-1, a series of agents targeting COX-2 and Topo I were designed by combining fenamates and phenols. The optimal compound 1H-30 displayed an enhanced inhibitory effect on COX-2 compared to tolfenamic acid and I-1 and showed better inhibition of Topo I than I-1. Importantly, 1H-30 showed potential anticancer effects and suppressed the activation of the NF-κB pathway in cancer cells. 1H-30 inhibited the nuclear translocation of NF-κB and suppressed the production of NO, COX-2, and IL-1ß in RAW264.7. In vivo, 1H-30 showed acceptable pharmacokinetic parameters, decreased the tumor growth without affecting the body weight, down-regulated COX-2 and MMP-9, and induced apoptosis in the CT26.WT tumor-bearing mice. Accordingly, 1H-30 as a potential Topo I/COX-2 inhibitor which possessed anti-inflammatory and anticancer effects, with inhibition of the NF-κB pathway, is promising for gastrointestinal cancer therapy.

Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy.

Natural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3'-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor activity. Among them, compound 8b revealed 55.15% and 55.50% inhibition for Top1 and Top2 at 25 µM, as well as 0.16 and 0.13 µM IC50 value for MGC-803 and SGC-7901 cells, respectively; compound 9a revealed 70.50% and 71.81% inhibition for Top1 and Top2 at 25 µM, as well as 0.22 and 0.27 µM IC50 value for MGC-803 and SGC-7901 cells, respectively. The further biological evaluation showed that they could functionally induce apoptosis, significantly arrest the cell cycle at the G2/M phase, and markedly inhibit cell proliferation, migration and invasion. In addition, compound 9a performed a tumor inhibitory rate of 36.35% and showed no apparent toxicity in vivo. Overall, these optimized protocols will advance the progression of cancer chemotherapy and can be used to expand the options for screening therapeutic cancer drugs.

Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents.

Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure-activity relationship studies. In vitro antiproliferative activity indicated that compounds F-3 and F-4 dramatically inhibited the proliferation of Huh7 (IC50 = 0.05 or 0.04 µM, respectively) and SK-Hep-1 (IC50 = 0.07 or 0.06 µM, respectively) cells. Furthermore, compounds F-3 and F-4 could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce apoptosis as well. Additionally, compounds F-3 and F-4 could also inhibit the activation of HSC-T6 and reduce the secretion of collagen type I to slow down the progression of liver fibrosis. Most importantly, compound F-4 (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound F-4 has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.

Isolation, synthesis and bioactivity evaluation of isoquinoline alkaloids from Corydalis hendersonii Hemsl. against gastric cancer in vitro and in vivo.

Isoquinoline alkaloid displays significant anti-gastric cancer effects due to its unique structure, which is attracting more and more attention for the development of anti-gastric cancer drugs. In this study, we explore the active components against gastric cancer from the Tibetan Medicine Corydalis hendersonii Hemsl, which is rich in isoquinoline alkaloids. 14 compounds including 2 previously undescribed natural products were obtained. Interestingly, an new active compound displays potent anti-gastric cancer activity. After accomplishing the total syntheses of the active compound and its derivatives, the anti-gastric cancer activity of the active compound was further investigated. In vitro experiments revealed that the active compound significantly attenuated the proliferative capacity, caused G2/M phase arrest, inhibited the cell migration and invasion, and induced cell apoptosis. Mechanistically, the active compound could increase the Bax/Bcl-2 ratio, elevate cytochrome c in the cytosol, and activate caspase-9/3, along with inactivating the upstream PI3K/Akt/mTOR signaling pathway. In addition, the active compound could also cause gastric cancer cell death by inhibiting topoisomerase I activity. More importantly, the anti-gastric cancer activity of the active compound was confirmed in MGC-803 xenograft nude mice in vivo. This work not only promotes the exploitation of Corydalis hendersonii Hemsl., but also provides some experience for discovering new entities from natural sources.